title: Identification of a new phenotype of tolerogenic human dendritic cells induced by fungal proteases from Aspergillus oryzae.
abstract: We characterized a new pathway to induce tolerogenic dendritic cells (DCs) following treatment of human monocyte-derived DCs with proteases from the fungus Aspergillus oryzae (ASP). ASP-treated DCs (ASP-DCs) exhibit a CD80(-)CD83(-)CD86(-)Ig-like transcript (ILT)2(-)ILT3(-)ILT4(+) phenotype, do not secrete cytokines or chemokines, and express tolerogenic markers such as glucocorticoid-induced leucine zipper, NO synthetase-2, retinaldehyde dehydrogenase-1 or retinaldehyde dehydrogenase-2. When cocultured with naive CD4(+) T cells, ASP-DCs induce an anergic state that can be reversed by IL-2. Generated T cells mediate a suppressive activity in third-party experiments that is not mediated by soluble factors. A comparison between dexamethasone-treated DCs used as a reference for regulatory T cell-inducing DCs and ASP-DCs reveals two distinct phenotypes. In contrast to dexamethasone, ASP treatment induces glucocorticoid-induced leucine zipper independently of glucocorticoid receptor engagement and leads to NF-κB p65 degradation. Abrogation of protease activities in ASP using specific inhibitors reveals that aspartic acid-containing proteases are key inducers of regulatory genes, whereas serine, cysteine, and metalloproteases contribute to NF-κB p65 degradation. Collectively, those features correspond to a previously unreported anergizing phenotype for human DCs. Such regulatory mechanisms may allow fungi to downregulate host immune responses and provide clues for new approaches to treat proinflammatory disorders.
authors.affiliation: Stallergènes, Antony Cedex 92183, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Zimmer
authors.forename: Sonia
authors.initials: S
authors.lastname: Luce
authors.forename: Fanny
authors.initials: F
authors.lastname: Gaignier
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nony
authors.forename: Marie
authors.initials: M
authors.lastname: Naveau
authors.forename: Armelle
authors.initials: A
authors.lastname: Biola-Vidamment
authors.forename: Marc
authors.initials: M
authors.lastname: Pallardy
authors.forename: Laurence
authors.initials: L
authors.lastname: Van Overtvelt
authors.forename: Laurent
authors.initials: L
authors.lastname: Mascarell
authors.forename: Philippe
authors.initials: P
authors.lastname: Moingeon
mesh_terms: D001236:Aspergillus oryzae / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D003907:Dexamethasone / Q000494:pharmacology; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics; D016130:Immunophenotyping; D010447:Peptide Hydrolases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D014162:Transfection
chemical_list: D006131:Growth Inhibitors; D003907:Dexamethasone; D010447:Peptide Hydrolases